Hormone-dependent mitochondrial resilience in leiomyoma cells exposed to oxidative stress.

Uterine leiomyomas persist and grow within a chronically pro-oxidant environment despite reduced antioxidant capacity, suggesting the existence of adaptive stress-tolerance mechanisms. Although estrogen and progesterone are well-established regulators of leiomyoma growth, their roles in coordinating mitochondrial function under oxidative stress remain poorly defined. Here, we investigated how estrogen and progesterone receptor signaling modulate oxidative stress-induced transcriptional programs and mitochondrial metabolic responses in uterine leiomyoma cells. Primary patient-derived leiomyoma spheroids were exposed to paraquat-induced oxidative stress in the presence of estradiol, progestins, or hormone receptor antagonists. Transcriptomic responses were assessed by RNA sequencing with differential expression and gene set enrichment analyses, while mitochondrial function was evaluated using Seahorse extracellular flux assays alongside measurements of senescence and cell viability. Estrogen and progesterone signaling reshaped oxidative stress-responsive gene expression programs linked to senescence, apoptosis, and mitochondrial regulation, which was evident with hormone receptor antagonism. Functional metabolic analyses revealed that hormonal signaling preserved mitochondrial maximal respiration and spare respiratory capacity under oxidative stress, while hormone blockade selectively impaired mitochondrial reserve capacity without compensatory glycolytic upregulation. Isoform-specific progesterone receptor effects further supported a role for differential receptor signaling in regulating mitochondrial adaptability. Together, these findings identify estrogen and progesterone receptor signaling as key regulators of mitochondrial stress tolerance in leiomyoma cells and support a model in which endocrine control of mitochondrial function enables cellular survival under sustained oxidative stress.